The long-term goals of this project are to understand the immunobiology of asthma and allergic disease. While our understanding of the role of Th2 responses in the pathogenesis of asthma as rapidly improved over the past 10 years, our knowledge of the mechanisms that dampen Th2 biased inflammatory responses and that protect against the development of Th2 inflammation and asthma remains rudimentary. Th1 cells may have a role in protection against allergy, however, our studies in murine systems indicate that multiple additional mechanisms play more critical roles in regulating asthma and allergy. We propose to identify and examine in detail these additional mechanisms that down-modulate Th2 responses in humans, and determine the cell types and molecules that participate in the protection against Th2-biased inflammation. We will identify the immunological mechanisms that prevent allergic diseases by examining allergic individuals who have successfully completed a course of allergen immunotherapy, as well as non-allergic individuals who are chronically exposed to inhaled allergen. These individuals tolerate exposure to inhaled allergen because they have developed allergen-specific protective immune responses, which we will study to gain insight into protective immunity against asthma and allergy. To assess immune responses in these non-symptomatic individuals, we will use new technologies, including gene expression profiling with cDNA microarrays and fluorescent staining with MHC class 11-peptide tetramers. By comparing gene expression profiles in cells from allergic individuals before and after allergen immunotherapy, and in cells from allergic and non-allergic individuals, we will develop a distinctive molecular portrait of the biology of, and identify specific genes and pathways important in, protective immunity. By using MHC class II-peptide tetramers; we will accurately quantitate changes in the frequency and function of allergen specific cells that occur with allergen immunotherapy. These studies, using cutting edge technologies and with collaborators who are leaders in their fields, will greatly extend our knowledge of immune responses that protect again asthma and allergy, and of Th2 biased immune responses that are pathologic for asthma and allergy. These studies therefore, are likely to lead to greatly improved therapies that protect against and potentially cure asthma and allergic diseases.